Almost all individuals diagnosed with high-grade brain tumors such as glioblastoma multiforme (GBM) will die of their disease as no effective therapies exist. These proposed studies will begin to explore how a novel immunotherapeutic strategy using adoptively transferred ?d T cells might be exploited for the treatment of GBM. Unlike the prolonged classical a[unreadable] T cell-mediated immune response which requires antigen processing and MHC-restricted display by antigen-presenting cells (adaptive immune response), ?d T cells can broadly recognize and immediately respond to a variety of MHC-like stress-induced self antigens (innate immune response). Human malignant GBM express many known target antigens for ?d T cells, and expanded/activated ?d T cells will lyse primary GBM and established GBM cell lines. Despite the in vivo cytotoxic effect of ?d T cells against GBM, there appears to be little effect against primary tumor in vivo -possibly due to lack of access to tumor, tumor-derived immunosuppression, or other factors that result in functional or numeric deficits in the ?d T cell compartment. Consequently we hypothesize that overcoming physical barriers and tumor-derived immune suppression will permit ?d T cells to mount an effective innate response to GBM. The test of this hypothesis is addressed in two specific aims. Studies conducted under the first specific aim will determine the extent to which ?d T cells from GBM patients will expand and kill established GBM cell lines and cultured cells from the patient's own GBM. This specific aim will examine the feasibility of autologous ?d T cell therapy for GBM. Studies conducted under specific aim 2 will determine whether or not ex vivo expanded/activated ?d T cells from healthy volunteers will kill established GBM cell lines and primary GBM cultures from the same patients accrued in Specific Aim 1. This specific aim will examine the feasibility of allogeneic ?d T cell therapy for GBM. Although no therapeutic interventions are proposed in this aim, we anticipate that this work will generate significant new preclinical data which will be essential for the design of our first generation clinical trials intended to examine how ex vivo expanded ?d T cells can be used as immunotherapy for GBM. At present, there is no effective treatment for glioblastoma multiforme (GBM), the most common malignant brain tumor. GBM is vulnerable to killing by a component of the immune system known as ?d T cells, but these cells appear to have little effect on the growing tumor. This is possibly because the ?d T cells cannot get to the tumor or because the tumor may itself prevent the ?d T cells from attacking it. We will test promising methods that may overcome these problems to determine if ?d T cells can be used as therapy against GBM without harming normal cells. If successful, we will then develop studies to treat human patients.